Breast cancer is the most common cancer among women worldwide and has a diverse range of characteristics [1,2]. Breast cancers can be classified based on molecular and histologic subtypes, reflecting their various characteristics [2,3]. Molecular subtypes are determined by the expression of estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2) amplification, and can be categorized into luminal A, luminal B, HER2-enriched, and basal-like types. Breast cancer treatment strategies are based on these classifications [4].

Even for rare types of breast cancer, treatment is determined by the expression of ER, PR, and HER2 as defined by the molecular subtype [5]. According to guidelines, such as those from the National Comprehensive Cancer Network (NCCN), treatment for rare histologic subtypes also depends on their molecular subtype [6]. For ER-positive tumors, hormonal therapy is recommended, and for HER2-positive tumors, a trastuzumab-based regimen is advised. Chemotherapy remains a valuable treatment option. However, in certain cases, treatment can be omitted based on prognosis, which is influenced by the histologic subtype [7]. Therefore, both molecular and histologic subtypes are essential factors in determining appropriate treatment strategies for breast cancer.

Breast cancer can be classified based on its histological features (Figure 1). According to the World Health Organization (WHO) classification revised in its 5th edition in 2019, approximately 75%–80% of breast cancers are classified as invasive carcinoma of no special type (NST), formerly known as invasive ductal carcinoma (IDC) [8]. The second most common histological type is invasive lobular carcinoma (ILC), which accounts for approximately 10%–15%. The remaining 5%–10% comprises rare histologic subtypes, collectively referred to as rare histologic breast cancers (Figure 2), representing between 0.1% and 2% of all breast cancer cases (Table 1) [9-12].

The 2019 WHO classification introduced significant changes, renaming IDC as invasive carcinoma of NST and incorporating various previously classified special subtypes under this category to simplify the classification for treatment purposes [8]. The invasive carcinoma of NST category encompasses diverse histological patterns, such as the medullary pattern, invasive carcinoma with neuroendocrine differentiation, carcinoma with osteoclast-like stromal giant cells, pleomorphic pattern, choriocarcinomatous pattern, melanocytic pattern, oncocytic pattern, lipid-rich pattern, glycogen-rich clear cell pattern, and sebaceous pattern [8]. Treatment for these subtypes should follow the ER/PR/HER2 status, which guides the management of most breast cancers according to established guidelines from organizations such as the NCCN, St. Gallen, and American Society of Clinical Oncology [13].

While most breast cancers follow these treatment patterns, certain rare subtypes may require different therapeutic approaches, which are further discussed in this review. This study did not aim to comprehensively address all the rare histologic subtypes of breast cancer. Instead, we focused on the key subtypes with active research and significant clinical implications. Specifically, we explored therapeutic approaches for subtypes such as mucinous carcinoma and secretory carcinoma, which have relatively good prognoses, as well as invasive micropapillary carcinoma (IMPC) and metaplastic breast carcinoma (MpBC), known for their poorer outcomes.

Mucinous carcinoma accounts for approximately 1%–7% of all breast cancers [14-16]. It is characterized by abundant extracellular and/or intracellular mucin production [17]. Mucinous carcinoma is classified as pure mucinous carcinoma, where >90% of the tumor consists of mucinous components, or as mixed mucinous carcinoma, which contains both mucinous and non-mucinous components [18]. Pure mucinous carcinomas account for approximately 2% of all cases of breast cancer [15]. According to a retrospective analysis by Skotnicki et al. [19], the risk of lymph node (LN) metastasis was higher in the mixed subtype (25%) than in the pure subtype (10%). Additionally, the 10-year disease-free survival (DFS) was significantly lower in the mixed subtype (65%) than in the pure subtype (85.7%), indicating a poorer prognosis in the mixed subtype. Treatment for mixed mucinous carcinoma follows the same principles as those for invasive carcinoma of NST [6]. Mucinous carcinoma generally exhibit favorable prognostic features, including 95% ER positivity, 84% PR positivity, and less than 10% HER2 positivity [20,21]. Most mucinous carcinomas belong to the luminal A subtype, which is associated with excellent prognosis. The reported survival rates were 94%, 89%, and 81% at 5, 10, and 20 years, respectively [16].

Due to its favorable prognosis, treatment typically involves breast-conserving surgery with sentinel LN biopsy, followed by adjuvant endocrine therapy. Chemotherapy is generally not recommended, unless LN metastasis is confirmed [6]. Large-scale retrospective studies from South Korea did not demonstrate a significant improvement in survival with chemotherapy; thus, chemotherapy is usually not recommended unless LN involvement is present. Adjuvant hormone therapy improved the DFS and overall survival (OS) [22].

Pure tubular breast cancer, which accounts for approximately 1%–2% of all breast cancers, is characterized histologically by single layers of newly formed epithelial cells with open lumina, comprising more than 90% of the tumor. Tubular carcinomas are generally low-grade [23]. In 95% of the cases, the tumor was ER-positive, with PR positivity observed in 69%, and HER2 expression was absent in 97% [24]. Pure tubular carcinoma is classified as a low-grade, well-differentiated, luminal A-type cancer associated with a favorable prognosis [25]. According to a large retrospective study based on the Surveillance, Epidemiology, and End Results database, the DFS and OS rates for pure tubular carcinoma were 98.1% and 92%, respectively [26]. This is superior even when compared to that of low-grade IDC [27]. Given its positive prognosis, adjuvant endocrine therapy is recommended, and chemotherapy may be added depending on LN status [23]. According to the NCCN guidelines, in cases where LNs are negative, adjuvant endocrine therapy alone is recommended, even for tumors >3 cm in size. However, adjuvant chemotherapy may be administered to patients with positive LNs [6].

Cribriform carcinoma is a rare subtype, accounting for approximately 0.3%–0.6% of all breast cancers [28-30]. It is characterized by a cribriform (sieve-like) pattern. When more than 90% of the tumor exhibits an invasive cribriform pattern, it is classified as pure cribriform carcinoma [11,29]. LN metastasis is rare, and the tumor generally presents at a lower stage, resulting in a better prognosis compared to more common types of breast cancer [31]. Most cribriform carcinomas are ER-positive and HER2-negative, with PR positivity observed in 69%–89% of cases [3,29]. Pure cribriform carcinoma has a 10-year survival rate of 90%–100%, which is superior to that of ILC [28,32]. Due to the limited benefits of chemotherapy for this subtype, adjuvant endocrine therapy is generally recommended. However, for cases with LN metastasis or mixed cribriform carcinoma, the treatment followed guidelines for invasive carcinoma of NST [6].

In ER-positive, HER2-negative breast cancer, gene panel studies such as Oncotype DX and MammaPrint are used to predict prognosis and determine the need for chemotherapy [6,33]. For histologic subtypes with a favorable prognosis, such as mucinous, tubular, and cribriform carcinomas, chemotherapy provides limited benefit; therefore, these genomic tests are generally not recommended [34]. However, not all cases are classified as low risk according to these gene panel studies. From February 2004 to August 2017, the Oncotype DX was used to analyze 610,350 tumor specimens. Of these, 16,116 (2.6%) were mucinous carcinomas, 3,599 (0.6%) were tubular carcinomas, and 1,897 (0.3%) were cribriform carcinomas. With a threshold score of 25, 9.4% of mucinous carcinomas, 3.2% of tubular carcinomas, and 7% of cribriform carcinomas were classified as high-risk, exceeding the 25-point threshold [35]. The standard systemic therapy for these cases is endocrine therapy, because chemotherapy generally provides limited benefits [6]. However, for a subset of patients identified as having a high genomic risk, a different therapeutic approach may be necessary.

Adenoid cystic carcinoma (ACC) is a rare tumor typically found in the salivary glands but can also occur in the breast, accounting for approximately 0.1% of breast cancers [36,37]. Histologically, breast ACC is indistinguishable from its salivary gland counterpart. Although ACC often exhibits features typical of TNBC, it has a more favorable prognosis [38]. In a study of 338 patients diagnosed with ACC between 1977 and 2006, the relative survival rates at 5, 10, and 15 years were 98.1%, 94.1%, and 91.4%, respectively [37]. Other studies have reported 10-year survival rates as high as 85%–100%, and LN metastasis is rare [38-40].

Secretory carcinoma is an extremely rare subtype of invasive breast cancer that accounts for less than 1% of all cases. This phenomenon was first described by McDivitt and Stewart (1966) [41,42]. While generally occurring in children and young adults, it has also been reported in older adults [43]. Histologically, secretory carcinoma presents with low-grade nuclei and intermediate cytoplasm, with cells containing intracellular and extracellular secretory material arranged in glandular, cystic, and solid nests separated by collagen bands to create a distinctive ‘honeycomb’ pattern [44]. LN metastasis has been reported in 15%–30% of cases, and despite the ER-negative and TNBC phenotypes of the tumor, it demonstrates an excellent prognosis, with a 10-year cancer-specific survival rate exceeding 90% [45-47].

Metaplastic carcinoma is generally associated with a poor prognosis. However, subtypes, such as low-grade adenosquamous carcinoma (LG-ASC) and low-grade fibromatosis-like carcinoma, have been associated with better outcomes. LG-ASC is typically associated with benign proliferative breast lesions such as complex sclerosing lesions and papilloma. Low-grade fibromatosis-like carcinoma is a variant of spindle cell carcinoma and has been reported in approximately 0.2%–1% of all breast cancers [11,48,49].

Despite their ER-, PR-, and HER2-negative immunohistochemical profiles on immunohistochemistry, these subtypes have a more favorable prognosis. The primary treatment is surgery, with systemic therapy being considered in cases of LN metastasis [6,50-52].

Studies support the omission of radiation therapy in certain cases, particularly in elderly patients with low-risk breast cancer. The Postoperative Radiotherapy in Minimum-risk Elderly II trial reported that, for low-risk, hormone receptor-positive breast cancer patients aged 65 years and older, especially those receiving endocrine therapy, omitting radiation therapy did not result in significant differences in DFS or OS [53]. However, omitting radiation therapy is not suitable for all patients. Even in breast cancers with a good prognosis, there may still be benefits from radiation therapy (RT). Research has shown that rare histological subtypes with favorable prognoses, including mucinous carcinoma, adenoid cystic carcinoma, and secretory carcinoma, can benefit from RT [54-57]. Although these subtypes have favorable prognoses, uniform omission radiation therapy is not advisable. Factors such as patient age, endocrine therapy status, and tumor size should be considered when making treatment decisions.

IMPC is a rare and aggressive subtype of breast cancer that represents approximately 0.9%–2% of all breast cancer cases [14]. Histologically, IMPC is characterized by clusters of malignant cells that maintain distinct stromal spaces, and often display reverse polarity in papillary structures without a central fibrovascular core [58]. Over 80% of IMPC cases are ER- or PR-positive, whereas HER2 positivity ranges from 30%–80% [59-61]. LN metastasis is frequently observed, even in small IMPC tumors [62]. Although IMPC is generally considered to have a poor prognosis due to its aggressive nature [63], a propensity-matched analysis found no significant difference in survival between IMPC and IDC [64]. Currently, no specific treatment guidelines exist for IMPC; therefore, treatment typically follows the protocols for invasive carcinoma of NST [6]. In HER2-positive IMPC, trastuzumab-based therapy is used; however, patients with HER2-positive IMPC have poor DFS outcomes. Mucin4 (MUC4), which is overexpressed in IMPC compared to IDC and ILC, is associated with trastuzumab resistance by masking HER2 epitopes, contributing to resistance to both ado-trastuzumab emtasine and trastuzumab deruxtecan (T-DXd) [65,66]. In clinical reports, patients with IMPC with mucinous features and micropapillary patterns showed the shortest PFS with T-DXd, suggesting that MUC4-induced masking may affect T-DXd efficacy [67]. Thus, HER2-positive IMPC may benefit from personalized treatment approaches, such as tumor necrosis factor-α inhibitors, to overcome resistance [65]. Additionally, neratinib, a pan-HER tyrosine kinase inhibitor, has shown efficacy in improving survival when administered as an adjuvant therapy after one year of trastuzumab-based treatment [68]. Given the overexpression of MUC4 in IMPC, neratinib may offer additional benefits to patients by overcoming trastuzumab resistance.

High-grade subtypes of metaplastic carcinoma represent approximately 1% of breast cancers and is associated with poor prognosis [69]. High-grade variants included squamous cell carcinoma, spindle cell carcinoma, and MpBC with heterologous mesenchymal differentiation. MpBC is distinguished by epithelial differentiation patterns that are not typically found in breast tissue, with over 90% of cases being ER-negative- and HER2-negative [70,71]. Clinically, MpBC is characterized by large tumor size and high histologic grade. The molecular profile of MpBC revealed basal-like or claudin-low subtypes, with genetic alterations in TP53, RB1, TERT promoter genes, chromatin remodeling genes (ARID1A and KMT2C), and pathways related to PI3K (PIK3CA, PIK3R1, PTEN), MAPK (NF1, KRAS, NRAS), and WNT (FAT1, APC, CCN6), which are associated with tumor progression and therapeutic resistance [72-74]. MpBC has a worse prognosis than IDC, with larger tumors and higher grades at diagnosis, making it more aggressive [75]. While chemotherapy is the standard systemic treatment for TNBC, MpBC often shows resistance to standard chemotherapy regimens, limiting treatment options [76].

MpBC typically has lower DFS and OS rates than the other TNBC subtypes [77,78]. Neoadjuvant chemotherapy is commonly used for locally advanced breast cancer, and MpBC is often diagnosed at an advanced stage, making it suitable for this treatment approach [79]. However, the effectiveness of neoadjuvant chemotherapy in MpBC is controversial because studies have shown that MpBC has significantly lower pathological complete response (pCR) rates than other subtypes, including TNBC. A large retrospective study using the National Cancer Database reported pCR rates of 9.8%, 23.8%, and 30.1% for MpBC, IDC, and TNBC, respectively [80]. Further analysis suggested no significant survival difference between ductal carcinoma and MpBC, with none of the 12 patients who received neoadjuvant chemotherapy achieving pCR and 41% of the patients showing disease progression. Based on these findings, researchers have recommended surgery instead of neoadjuvant chemotherapy as the first-line treatment for MpBC [81]. In a study by Wong et al. [82], 44 patients who received neoadjuvant chemotherapy were analyzed; 27% experienced disease progression and only 2% achieved pCR. Thus, surgery is recommended as the primary treatment option for MpBC unless it is inoperable. Patients with MpBC who achieved pCR showed excellent outcomes, similar to those of patients with IDC with pCR, whereas patients with MpBC without pCR had significantly worse survival rates [80].

MpBC has been reported to express Programmed Death-Ligand 1 (PD-L1) in 46% of cases, a higher rate than seen in other breast cancer subtypes [83]. In PD-L1-positive TNBC, pembrolizumab has been shown to improve survival, and neoadjuvant pembrolizumab therapy has been proven to increase pCR rates, making it a widely used treatment option [84,85]. Adams et al. [86] reported a remarkable response to pembrolizumab combined with nab-paclitaxel in unresectable metastatic MpBC. In another case, Gul et al. [87] described a patient who achieved pCR with neoadjuvant chemotherapy comprising pembrolizumab, paclitaxel, carboplatin, doxorubicin, and cyclophosphamide.

Breast cancer comprises many rare histological subtypes, most of which are treated according to the ER, PR, and HER2 status based on established treatment protocols. However, standard therapies may be ineffective for rare subtypes, particularly those with a poor prognosis. Limited clinical data and research on these subtypes have restricted the development of tailored treatment strategies.

To overcome these challenges, increased collaborative research is needed to better understand the pathological and molecular characteristics of rare breast cancer subtypes. Identifying novel biomarkers and integrating them into clinical practice could enable more personalized and effective treatment options. Ultimately, these efforts could significantly improve the survival rate and quality of life of patients with rare forms of breast cancer.